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Cholinergic Drug Improves Cognition in Nonsmokers With Schizophrenia

28 September 2012. Genetic, behavioral, and neurophysiological evidence has converged to implicate dysfunctional α7 nicotinic acetylcholine receptors (nAChRs) in neurocognitive symptoms of schizophrenia. In a short preliminary study published in the September issue of The American Journal of Psychiatry, researchers found that the α7 agonist tropisetron improved cognition and rescued a neural measure of cognitive function.

The α7 subtype of nAChR modulates sensory gating, including the inhibitory P50 evoked response to repeated auditory stimuli; deficits in this response, which some researchers believe may contribute to the disordered thought processes characteristic of schizophrenia, is a well-replicated endophenotype seen in the illness.

Animal studies and smaller-scale human trials have suggested that the P50 deficit, and overall cognitive function, might be normalized by α7 nAChR agonists (for a review, see AhnAllen, 2012; also see SRF related news story), though there have been mixed results with one such agonist, DMXB-A (Olincy et al., 2006; Freedman et al., 2008; also see SRF related news story; SRF news story). However, this therapeutic strategy has now gained some new legs from a study by Thomas and Therese Kosten and lead author Xiang Yang Zhang at Baylor College of Medicine and colleagues in Shantou, Zhongshan, Beijing, and Nanjing, China.

Nonsmoking Chinese patients with schizophrenia who had received comparable doses of risperidone for one month were tested for the P50 response and for overall cognitive functioning with a Mandarin translation of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Forty patients exhibited significant deficits in the P50 response and were randomized to receive either placebo or a 5, 10, or 20 mg dose of tropisetron, a high-affinity partial agonist of the α7 nAChR, for 10 days. On day 10, the P50 response was measured in all groups, and the RBANS was administered again.

All three treatment groups had significant improvements on the RBANS over the placebo group, both in RBANS total scores and on scores measuring particular cognitive functions (though patients in the 10-mg group showed better performance on immediate memory than the placebo group, while those in the 20-mg group were significantly better at delayed memory tasks). Significant effects on the inhibitory P50 response were also seen in all treatment groups compared to the placebo group, and there was a significant correlation between cognitive improvement as measured by the RBANS and normalization of the P50 response.

In an aside, the researchers also report striking anecdotal evidence for tropisetron’s therapeutic effects: without prompting by investigators, about half of the patients who received the drug spontaneously “remarked that they could think more clearly or concentrate better and could remember things easier or better.”

The authors consider the combined results to be sufficiently encouraging to “strongly support” launching a trial enrolling a larger number of patients tropisetron’s effects on P50 gating and on cognition over a longer term; such a trial is now under way.—Pete Farley.

Reference
Zhang XY, Liu L, Liu S, Hong X, Chen da C, Xiu MH, Yang FD, Zhang Z, Zhang X, Kosten TA, Kosten TR. Short-term tropisetron treatment and cognitive and p50 auditory gating deficits in schizophrenia. Am J Psychiatry. 2012 Sep 1;169(9):974-81. Abstract

Comments on News and Primary Papers
Comment by:  Britta Hahn
Submitted 7 October 2012
Posted 7 October 2012

The study by Zhang et al. (2012) provides further evidence for the therapeutic potential of partial α7 nicotinic acetylcholine receptor (nAChR) agonists in the treatment of the cognitive deficits associated with schizophrenia. Given the impact of this symptom group on psychosocial functioning (Green et al., 2004; Tan, 2009) and the current absence of effective treatments, the importance of such findings is easily seen. Tropisetron administered over 10 days improved immediate and delayed memory subscales of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and improved P50 auditory gating deficits in 40 non-smoking inpatients with schizophrenia.

The evidence for enhanced auditory gating was strong, with the reduction in the S2/S1 ratio being entirely due to a decrease in S2 amplitude with no change in S1. By limiting the study sample to patients who displayed P50 gating deficits at baseline (~40 percent of all screened patients), the authors may have selected a subpopulation of patients particularly prone to showing benefits from α7 nAChR agonist treatment, possibly due to a larger incidence of genetic mutations reducing α7 nAChR subunit expression (Leonard et al., 2002) in this subsample. This type of pre-screening may indeed be a clinical approach to be considered prior to α7 agonist treatment. However, the measurement reliability of the P50 S2/S1 ratio tends to be low, and the degree to which P50 gating deficits predict treatment success with α7 agonists remains to be determined. Despite the large role that this ERP has played as an endophenotype of schizophrenia guiding drug development, evidence that P50 gating deficits are related to higher cognitive functions is still sparse (Potter et al., 2006). Zhang et al. found that changes in P50 gating from baseline to day 10 were correlated with changes in RBANS scores, collapsing data across all four treatment groups (including placebo). However, such correlations may be based on day-to-day fluctuations in cognitive state that could affect both measures in the same manner. More evidence is needed to clarify the clinical significance of improvements in P50 gating.

The finding that effects of tropisetron were seen mostly on memory indices differs from studies with the partial α7 agonist DMXB-A (Olincy et al., 2006; Freedman et al., 2008) and a previous study with tropisetron (Shiina et al., 2010), which reported effects predominantly on attention/vigilance indices. Larger trials may be able to determine more conclusively the cognitive domains beneficially affected by α7 agonists. Relatively flat dose-response curves were observed with tropisetron, consistent with a partial agonist mode of action. The finding that the largest dose (20 mg) produced no added benefits but tended to be associated with more side effects argues for the choice of lower doses.

Caution is warranted to not let positive findings with α7 agonists convey the impression that non-α7 nAChR subtypes are irrelevant for the treatment of cognitive deficits in schizophrenia. Indeed, non-α7 subtypes such as α4β2 mediate beneficial effects of nAChR agonists on cognitive performance (e.g., Dunbar et al., 2007; Grottick et al., 2003; Hahn et al., 2003; Levin, 2002), including improvements in sensory gating (Radek et al., 2006). The advantage of targeting α7 over other nAChR subtypes remains to be established by direct comparison. There is also a need for direct comparisons of α7-selective agonists with broader acting nAChR agonists to determine whether this subtype captures all cognitive benefit to be harvested from nAChR modulation in the treatment of schizophrenia.

References:

Dunbar G, Boeijinga PH, Demazières A, Cisterni C, Kuchibhatla R, Wesnes K, Luthringer R (2007) Effects of TC-1734 (AZD3480), a selective neuronal nicotinic receptor agonist, on cognitive performance and the EEG of young healthy male volunteers. Psychopharmacology 191: 919-29. Abstract

Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L, Allensworth D, Guzman-Bonilla A, Clement B, Ball MP, Kutnick J, Pender V, Martin LF, Stevens KE, Wagner BD, Zerbe GO, Soti F, Kem WR. (2008) Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry 165: 1040-7. Abstract

Green MF, Kern RS, Heaton RK (2004) Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res 72: 41-51. Abstract

Grottick AJ, Haman M, Wyler R, Higgins GA (2003) Reversal of a vigilance decrement in the aged rat by subtype-selective nicotinic ligands. Neuropsychopharmacology 28: 880-7. Abstract

Hahn B, Sharples CG, Wonnacott S, Shoaib M, Stolerman IP (2003) Attentional effects of nicotinic agonists in rats. Neuropharmacology 44: 1054-67. Abstract

Leonard S, Gault J, Hopkins J, Logel J, Vianzon R, Short M, Drebing C, Berger R, Venn D, Sirota P, Zerbe G, Olincy A, Ross RG, Adler LE, Freedman R (2002) Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. Arch Gen Psychiatry 59: 1085-96. Abstract

Levin ED (2002) Nicotinic receptor subtypes and cognitive function. J Neurobiol 53: 633-640. Abstract

Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, Ellis J, Zerbe GO, Leonard S, Stevens KE, Stevens JO, Martin L, Adler LE, Soti F, Kem WR, Freedman R. (2006) Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 63: 630-8. Abstract

Potter D, Summerfelt A, Gold J, Buchanan RW (2006) Review of clinical correlates of P50 sensory gating abnormalities in patients with schizophrenia. Schiz Bull 32: 692-700. Abstract

Radek RJ, Miner HM, Bratcher NA, Decker MW, Gopalakrishnan M, Bitner RS (2006) Alpha4beta2 nicotinic receptor stimulation contributes to the effects of nicotine in the DBA/2 mouse model of sensory gating. Psychopharmacology 187: 47-55. Abstract

Shiina A, Shirayama Y, Niitsu T, Hashimoto T, Yoshida T, Hasegawa T, Haraguchi T, Kanahara N, Shiraishi T, Fujisaki M, Fukami G, Nakazato M, Iyo M, Hashimoto K (2010) A randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia. Ann Gen Psychiatry 9: 27. Abstract

Tan BL (2009) Profile of cognitive problems in schizophrenia and implications for vocational functioning. Aust Occup Ther J 56: 220-228. Abstract

View all comments by Britta HahnComment by:  Georg Winterer (Disclosure)
Submitted 30 October 2012
Posted 30 October 2012

The paper of Zhang et al. once more presents promising findings suggesting that nicotinic α7 (partial) agonists may eventually be used as cognition enhancers in schizophrenia. Since several completed studies about the effect of nicotinic agonists on P50 gating and cognitive parameters are now around, we should try to figure out what distinguishes the negative and positive studies.

In the particular case of tropisetron, it certainly needs to be acknowledged that this drug also is a serotonin 5-HT3 antagonist. Previous studies (e.g., Adler et al., 2005) have already suggested that drugs that act as antagonists at this receptor improve P50 gating. Since antagonism of 5-HT3 increases release of acetylcholine, this may add to the direct partial agonist effect of tropisetron at the (low affinity) α7 nicotinic receptor as well as other nicotinic receptors, including high-affinity α4β2 receptors. In this regard, we should also acknowledge that agonists that act at other nicotinic receptors (α4β2) are now under investigation and show promising results when it comes to cognition enhancement in schizophrenia (e.g., varenicline).

Varenicline is primarily a partial agonist of the α4β2 subtype (although agonism at α7 has also been reported). Notably, other than tropisetron, varenicline is an agonist of 5-HT3 receptors. This is puzzling, adding to the confusion about the true cognition-enhancing effect in cholinergic drugs. It might be (exclusively) α7, but it is too early to jump to this conclusion. For instance, we recently published a negative proof-of-mechanism study on allosteric α7 nicotinic receptor modulation and P50 sensory gating in schizophrenia (Winterer et al., 2013).

In my opinion, what we need now is to go back to healthy probands (Phase 1) and select a range of drugs with different receptor profiles, but which have in common that they all act directly or indirectly at nicotinic receptors. These drugs then should be systematically tested for their effects on electrophysiological surrogate measures, including P50 gating, as well as cognitive measures, followed by corresponding investigations (using a preselected subset of compounds) in schizophrenia patients. Of course, this would require collaboration between R&D of different pharmaceutical companies—in other words: an industrial network approach is the unmet need!

References:

Adler LE, Cawthra EM, Donovan KA, Harris JG, Nagamoto HT, Olincy A, Waldo MC. Improved p50 auditory gating with ondansetron in medicated schizophrenia patients. Am J Psychiatry . 2005 Feb ; 162(2):386-8. Abstract

Winterer G, Gallinat J, Brinkmeyer J, Musso F, Kornhuber J, Thuerauf N, Rujescu D, Favis R, Sun Y, Franc MA, Ouwerkerk-Mahadevan S, Janssens L, Timmers M, Streffer JR. Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: A proof-of-mechanism study. Neuropharmacology . 2013 Jan ; 64(1):197-204. Abstract

View all comments by Georg Winterer

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Related News: Nicotinic Receptor Agonist Shows Promise in Pilot Study

Comment by:  Robert W. Buchanan
Submitted 5 July 2006
Posted 5 July 2006

In light of the limitations of first- and second-generation antipsychotics and other pharmacological agents for the treatment of cognitive impairments in schizophrenia, the demonstration of an acute benefit of DMXB-A for cognitive performance and sensory gating is of considerable potential interest. Patients with schizophrenia are characterized by a broad range of cognitive impairments (Nuechterlein et al., 2004). These impairments have been shown to be a major determinant of poor functional outcome (Green et al., 2004). The NIMH has made a substantial commitment to facilitate the development of new pharmacological treatments for cognitive impairments through their funding of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia (TURNS) initiatives. The MATRICS process selected the α7 nicotinic receptor as one of the top targets for the treatment of cognitive impairments in patients with schizophrenia (Geyer and Tamminga, 2004).

In the current study, 12 subjects with schizophrenia were administered DMXB-A, an α7 nicotinic receptor partial agonist. The study was designed to assess the proof of concept that increased stimulation of the α7 nicotinic receptor would enhance performance on a cognitive battery and improve sensory gating, as measured by the P50 dual click paradigm. There is extensive preclinical and clinical rationale for this approach, but few drugs are available to directly assess the efficacy of the approach. The results clearly support the benefit of this approach, but a number of questions will need to be addressed in future studies before the ultimate utility of this approach is known. The most important issue is whether the acute efficacy observed with essentially a single dose will translate to a persistence of an effect with chronic drug administration. Tachyphylaxis develops rapidly with repeated stimulation of the α7 nicotinic receptor. Preclinical data suggest that this may not be an issue with DMXB-A, but long-term exposure data are required to directly address this issue. Second, two DMXB-A doses were evaluated. The results were different between the two doses, but how different is unclear, because of the small sample size. Preclinical data suggest that α7 nicotinic receptor partial agonists may show an inverse u-shaped response curve. The loss of efficacy at higher doses underscores the importance and potential difficulty in delineating the most effective dose range. Third, subjects who used nicotine products in the last month were excluded from the study. Patients with schizophrenia who do not smoke cigarettes are in the minority, and perhaps represent less than a third of the total population. The question of whether the beneficial effect of the drug would generalize to patients who smoke cigarettes will eventually need to be evaluated. Finally, the most pronounced effect was observed for the RBANS attention index. This effect is consistent with previous studies of acute nicotine administration in patients with schizophrenia. Future studies will need to evaluate whether the effect of DMXB-A is largely limited to attention or whether it will have significant benefit for other cognitive domains.

In summary, the demonstration that the acute administration of DMXB-A produces improved performance on a neuropsychological battery is an important first step in developing a novel therapeutic approach for one of the most critical areas of schizophrenia therapeutics.

References:

Nuechterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF, Heaton RK. Identification of separable cognitive factors in schizophrenia. Schizophr Res. 2004; 72: 29-39. Abstract

Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res. 2004;7 2: 41-51. Abstract

Geyer MA, Tamminga CA. Measurement and treatment research to improve cognition in schizophrenia: neuropharmacological aspects. Psychopharm. 2004; 174: 1-2.

View all comments by Robert W. Buchanan

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Comment by:  Patricia Estani
Submitted 6 July 2006
Posted 6 July 2006
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